The invention relates to pharmaceutical compositions for the treatment and/or prevention of Helicobacter pylori-associated disorders and to methods of treating such disorders in patients in need thereof.
Helicobacter pylori (H. pylori) infection is associated with several benign and malignant human diseases [Dooley CP, et al., N Engl J Med (1989) 321:1562-1566; Carrick J, et al., Gut (1989) 30:790-797; Nomura A, et al., N Engl J Med (1991) 325:1132-1136 [see comments]; Nomura A, et al., Ann Intern Med (1994) 120:977-981 [see comments]; Zucca E, et al., N Engl J Med (1998) 338:804-810]. However, symptomatic infection is only the tip of the iceberg, the majority of infected individuals remain asymptomatic. Moreover, if untreated, infection may last for decades [Peterson W L and Harford W V, (1991) 86:671-675], representing a successful host-parasite relationship. This favorable interaction is reflected in a high prevalence of infection ranging between 50% in developed to 90% in developing countries [Graham D Y, et al. Dig Dis Sci (1991) 36:1084-1088; Taylor D N and Blaser M J, Epidemiol Rev (1991) 13:42-59].
H. pylori resides within the mucous layer of the human gastric mucosa. Due to extremely low pH, the stomach is a hostile environment to most other microorganisms. The ability of H. pylori to flourish in the stomach has been attributed to protective mechanisms such as its production of urease, protecting the bacterium from gastric acidity by creating a basic microenvironment [Taylor D N and Blaser M J, Epidemiol Rev (1991) 13:42-59]. However, it has now been reasoned, that H. pylori might have evolved a way to gain growth advantage in this particular niche of the stomach, possibly by exploiting a gastric factor. A logical candidate would be one that is upregulated by H. pylori infection.
One such factor is the gastric hormone gastrin. Gastrin is produced as a prohormone by G cells located within the gastric antrum. The prohormone is later processed to shorter peptides, the most abundant of which is 17 amino acids long, termed gastrin 17 (G17) [Eaton K A, et al, Infect Immun (1991) 59:2470-2475]. The major role attributed to gastrin within the gastric tissue is the regulation of acid secretion. Following infection, gastrin levels are found to be consistently elevated and normal physiologic negative feedback control of secretion is lost. Further, following H. pylori eradication, gastrin levels are reduced and normal feedback control of gastrin secretion is restored [Graham D Y, et al., Am J Gastroenterol (1990) 85:394-398; El-Omar E, et al., Gut (1993) 34:1060-1065 [see comments]; Konturek J W, et al, Gut (1995) 37:482-487].
Interest in the changes of gastrin secretion and control have been directed to its role in acid production, and the resulting peptic pathology. However, the present work was focused on the possible interactions between gastrin and H. pylori. 
As will be shown hereafter, gastrin positively stimulates the growth of H. pylori, a finding which further exemplifies the successful adaptation of H. pylori to the human host, and provides the basis for the present invention.
The present invention relates to pharmaceutical compositions for the treatment and/or prevention of H. pylori-associated disorders comprising as active ingredient a therapeutically effective amount of a compound which inhibits the growth-enhancing effect of gastrin on H. pylori, particularly H. pylori-associated gastrointestinal disorders, such as H. pylori-associated gastric and/or duodenal peptic diseases. The pharmaceutical compositions of the invention may optionally further comprise pharmaceutically acceptable carriers, adjuvants or diluents.
The active ingredient in the pharmaceutical compositions of the invention may be a compound which is capable of inhibiting gastrin uptake by H. pylori, particularly compounds which are competitive inhibitors of gastrin uptake by H. pylori, or antagonists of the human or H. pylori gastrin receptor. In preferred embodiments, the active compound in the pharmaceutical compositions of the invention is a peptide. Preferred peptides are synthetic analogues of gastrin or of a fragment of gastrin, preferably of G17, and most preferred are peptides comprising the amino acid sequence: Trp-Met-Asp-PheNH2 (SEQ ID NO:1), such as pentagastrin or cholecystokinin (CCK)-8.
In other embodiments the pharmaceutical compositions of the invention may comprise as the active ingredient a non-peptidic antagonist of the human or H. pylori gastrin receptor.
In yet a further aspect, the invention relates to a method for the treatment and/or prevention of H. pylori-associated disorders in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound which inhibits the growth-enhancing effect of gastrin on H. pylori or a therapeutically effective amount of a composition according to the invention.
The method of the invention may be used for the treatment and/or prevention of H. pylori-associated gastrointestinal disorders.
Yet further, the invention relates to use of a compound which inhibits the growth-enhancing effect of gastrin on H. pylori in the preparation of a pharmaceutical composition for the treatment of H. pylori-associated disorders. In the use according to the invention, the said compound may be a synthetic analogue of G17, preferably comprising the amino acid sequence: Trp-Met-Asp-PheNH2 (SEQ ID NO:1). Alternatively, the compound may be a non-peptidic antagonist of the human or H. pylori gastrin receptor.